Combined bioavailable isoflavones and probiotics improve bone status and estrogen metabolism in postmenopausal osteopenic women: a randomized controlled trial.

Randomized controlled trial in postmenopausal women with osteopenia recruited from northern Denmark. The active red clover extract group had a mean age of 60.84 ± 1.07 years; participants were not receiving osteoporosis pharmacotherapy during the trial.

Oral fermented red clover extract rich in isoflavone aglycones, given twice daily as 2 × 95 mL for 12 months, providing 60 mg isoflavone aglycones/day. The active extract also contained probiotic lactic acid bacteria, and the regimen was compared against placebo while both groups received background calcium, magnesium, and calcitriol supplementation.

Overall, the bioavailable red clover isoflavone plus probiotic regimen was beneficial and well tolerated, with no adverse events reported. It favorably shifted estrogen metabolism: the urinary 2-OH:16a-OH ratio increased from 2.77 ± 0.19 to 3.41 ± 0.23 in the active group, versus 3.13 ± 0.27 to 2.98 ± 0.17 in controls, with an intergroup difference of P < 0.05. Equol production also increased, with 55% (n = 21) classified as equol producers at 6 months and equol concentration reaching 39.80 ± 15.68 nmol/L versus 3.02 ± 0.67 nmol/L in controls. Bone turnover also improved, with CTx decreasing from 0.44 ± 0.03 to 0.39 ± 0.16 ng/mL (change -0.04, 95% CI -0.09 to 0.01; P < 0.05), and the authors concluded that the intervention markedly attenuated estrogen-deficiency-related bone mineral density loss.

The trial was conducted in a specific group of postmenopausal osteopenic women from one region, limiting generalizability. The active arm sample size is not stated in the extracted source, and several biomarkers did not show significant between-group differences. Because calcium, magnesium, and calcitriol were co-administered, the effect cannot be attributed to the red clover extract alone.